The acid-base balance of the body is an essential factor to the adequate regulation of metabolic processes, and the disturbance of this balance is frequently jeopardized by diseases as well as lifestyle habits of our age, for example stress, inappropriate nutrition, harmful practices and addictions.
A neutral or slightly alkaline pH is required in the duodenal lumen and in the further parts of the small intestine for many reasons.
For example the pH of the duodenal lumen or its change is a particularly important regulating factor of the gastric emptying, since the prolonged acid load of the duodenum delays emptying the food partly digested and converted into pulp in the stomach, i.e. the chymus, into the duodenum. The persistent prolongation of the approximately three-hour physiological gastric transit time causes disturbances in the motoric and secretory functions of the whole alimentary canal.
In addition, the optimum of the normal function of the approximately twenty “luminal” pancreatic digestive enzymes secreted into the duodenal lumen and present in the upper third of the small intestine, is in the pH range of 6.5 to 8.7, and orally added digestive enzymes also need this optimal chemical environment.
The inactivation of pepsins also takes place in the duodenal lumen at this pH, which is required to protect the small intestinal mucosa and the luminal pancreatic digestive enzymes.
Moreover, the alkaline environment promotes the emulsification of the lipid aggregates and the micelle-forming, the protection of the small intestinal mucosa, including the carbon dioxide/bicarbonate cycle, which takes place in the mucin layer adhered to the intestinal mucosa.
As it was mentioned above, this optimal pH environment promotes the adequate gastric motility and emptying, thereby alleviates the disturbances of the motoric and neuroendocrine-exocrine regulatory and secretory functions of the whole alimentary canal in various clinical scenarios.
Accordingly, the neutral or slightly alkaline pH range promotes the luminal phase digestion and food absorption, which may help to avoid the harmful effects caused by the huge amount of improperly digested food remained in the lumens of the small intestine and the colon as a consequence of the inadequate luminal digestion, which may contribute to the following clinical scenarios or cause transient or permanent disorders, for example:                Absorption disorders, deficiency diseases (vitamins, trace elements, etc.) and as a consequence, decline in the resistance of the organism,        Increased osmotic pressure in the lumen of the small intestine and the colon,        Allergic, cellular and humoral immunoreactions caused by improperly digested food fragments (peptides, hydrocarbons, etc.),        Gastrointestinal disbacteriosis and absorption of toxic products caused by the condition,        Increased intestine mucosal permeability, which promotes the absorption of toxic byproducts as well as immunoreactions,        Irritation of the intestinal mucosa,        Disturbance of the enterohepatic circulation of bile acids,        abdominal complains caused by prolonged transit time and increased gas formation, for example discomfort, distention, pains, defecation complaints, etc.        
It is important to note that the contradictions are negligible as compared to the scope of the indication field of bicarbonate, which contradictions are e.g. hypernatraemia, which is responsible to treatment, further, infrequent metabolic and respiratory alkalosis and respiratory acidosis.
If the acid-base balance of the gastrointestinal system is disturbed and the partially digested food mixed with gastric acid (gastric content or chymus) enters the duodenum without being neutralized, that is, without creating a near neutral or slightly alkaline gastric environment, the entering chymus makes the upper part of the small intestine acidic, which causes disturbances primarily in the digestion processes taking place in the duodenum, as mentioned above.
Earlier, these disturbances were treated for example by orally administered sodium bicarbonate (its exact chemical name: sodium hydrogen carbonate), i.e. by delivering it directly into the gastric lumen. In the present description sodium hydrogen carbonate is called sodium bicarbonate or simply bicarbonate in accordance with the therapeutic practice.
Bicarbonate and its metabolites, namely carbonic acid or carbon dioxide and water are essential and, within wide physiological ranges, not toxic elements of the vital processes.
Theoretically, bicarbonate can be used orally for the neutralization of the gastric acid or the acidic chymus, since the organism also uses bicarbonate secreted by the pancreas, the liver and the intestinal wall, for the neutralization of the gastric acid. However, under physiological circumstances, this process occurs primarily in the duodenum and the upper part of the small intestine rather than in the gastric lumen.
Owing to the absolute or relative bicarbonate deficit developed in the duodenal lumen for any reason (like transient or permanent deviations from a healthy lifestyle and functional disorders or diseases, parenchymal injuries) the duodenum/small intestine is subjected to an increased acid load.
In the point of view of the pharmaceutical technology, the per os use of sodium bicarbonate is challenging, because its dissolution have to be prevented in the gastric fluid, since the hydrochloric acid present in the stomach immediately neutralizes the bicarbonate, meanwhile gas develops, which causes tonicity and distension and may involve even greater risks in the case of a tense stomach or higher doses. For these reasons using bicarbonate in the stomach is contradicted, as mentioned above.
To avoid this, various enterosolvent bicarbonate containing compositions were developed. For example bicallorm tablets (Fresenius Medical Care Deutschland GmbH, Homburg, DE) and Nephrotrans capsules (Medice Arzneimittel Pütter GmbH & Co. KG, Iserlohn, DE) are on the market. In vitro modeling of the release of the active agent from these compositions and other compositions were disclosed by Breitkreutz at all [“Enteric-Coated Solid Dosage Forms Containing Sodium Bicarbonate as a Drug Substance: an Exception from the Rule?” JPP, 59: 59-65 (2007)].
The presently known compositions provided with enterosolvent coatings resist to the acidic environment and start to release the active agent at neutral or higher pH values. This effect is accomplished by the use of polymer coatings soluble above pH 6. Polymers applicable for this purpose are for example cellulose acetate, hydroxypropyl methylcellulose phthalate, carboxymethyl ethylcellulose, polyvinyl acetate phthalate and polymethacrylate.
Some of the pharmaceutical compositions disclosed in the literature release the active agent gradually, as they move along in the increasing pH environment of the intestines. However, these compositions also exert their effects above pH 6. For example in Patents CA2352496 and U.S. Pat. No. 7,022,345, respectively, Valducci disclosed oral pharmaceutical formulations showing pH-dependent multiphasic release of active agent Mesalazine.
The above-mentioned marketed enterosolvent pharmaceutical formulations release their active agents at neutral or basic pH values, that is, in the farther parts of the small intestine. Accordingly, they cannot be used for treating or preventing the harmful effects appearing in the duodenum and in the first part of the jejunum, such as digestive, functional, dyspeptic troubles, motility disorders and mucosal irritation.
The object of our work was to develop a pharmaceutical composition that resists to the highly acidic environment of the stomach, but is able to release its bicarbonate content in pH-dependent, gradual and sustained manner in slightly acidic environment, while moving on together with the intestinal content, thereby increasing the pH of the acidified parts of the intestines.
The considerable difficulty with coatings soluble in slightly acidic pH is however that the polymer coating begins to swell at a strongly acidic pH, and when moisture reaches the particle core, the pH on the surface of the alkaline active agent may locally exceed the lowest pH value at which the polymer is soluble, consequently, the coating starts to erode from inside, which leads to an early, uncontrolled and irreproducible release of the active agent.
Therefore it was a great challenge to elaborate the highly reproducible pharmaceutical composition according to the present invention.
General Description of the Invention
The invention concerns a pH-dependent gradual sustained release pharmaceutical composition usable for increasing the pH in the upper third of the small intestine.
The pharmaceutical composition according to the invention comprises at least a first and a second type of microparticles having multilayer enterosolvent coatings, the cores of the microparticles comprising sodium hydrogen carbonate and said multilayer coatings comprising at least a cationic polymer coating contacting the core, a pH-independent polymer coating and a pH-dependent soluble anionic polymer coating, wherein the coating of the first type of microparticles is resistant to acidic pH below a well defined first pH threshold value but disrupts above this pH threshold value, and the second type of microparticles is resistant to acidic pH below a well defined second pH threshold value but disrupts above this second pH threshold value, wherein said second threshold value is at least 0.5 pH unit higher than said first threshold value.
In a preferred embodiment the composition according to the present invention comprises microparticles provided with the coating layers shown in FIG. 1. Accordingly, the first type of microparticles comprises                a cationic polymer coating insoluble above pH 5 (coating “a”),        a polymer coating soluble at pH≧6 (coating “A”),        a pH-independent polymer coating (coating “B”) and        an anionic polymer coating soluble at pH≧4.5 (coating “C”), and the second type of microparticles comprises        a cationic polymer coating insoluble above pH 5 (coating “a”),        a polymer coating soluble at pH≧6 (coating “A”),        a pH-independent polymer coating (coating “B”) and        an anionic polymer coating soluble at pH≧5.5 (coating “D”).        
Preferably, the coating layers of the microparticles according to the invention comprise the following polymers: coating “a” comprises an aminoalkyl methacrylate copolymer, coating “A” comprises a copolymer of methacrylic acid and methacrylate, coating “B” comprises a copolymer of ethyl acrylate and methyl acrylate, coating “C” comprises hydroxypropyl methylcellulose phthalate and coating “D” comprises a copolymer of methacrylic acid and ethyl acrylate.
In another preferred embodiment the ratio of the first and second types of microparticles of the composition according to the invention is 20/80 to 80/20.
In another preferred embodiment the composition according to the invention is filled in gastrosolvent capsules.
The invention also covers a process for the preparation of the composition according to the invention, which comprising preparing the particle cores from the active agent(s) and commonly used pharmaceutical additives using an alcoholic granulation process under anhydrous conditions, and applying the coating layers consecutively thereon, where coatings “a” and “A” are applied in the form of alcoholic solutions and coatings “B”, “C” and “D” are applied in the form of aqueous solutions or dispersions. After that the various types of microparticles are mixed in a required ratio and optionally filled into gastrosolvent capsules.